Physiological cooling agents are used in topical formulations to impart a cooling sensation to the skin. These do not actually cool the skin temperature but interact with the cold and hot receptors present in the skin to give the individual the perception of a cool or warm feeling. The exact mechanism of the interaction between the cooling agent and the nerve receptors is not fully understood but, without wishing to be bound by theory, it is believed that physiological cooling agents affect calcium channels or the calcium transport associated with a number of receptors found in the skin. This interaction causes a greater stimulation of the nerve receptors giving rise to the perception of cold or hot.
Menthol is probably the best known of all the physiological cooling agents and is obtained from various species of mint plant (e.g. Mentha arvensis). Menthol is relatively cheap and effective but has the disadvantage that it has a strong mint-like odour. In addition, the cooling or warming lasts for a relatively short period of time when applied to skin, typically, one or two hours.
A number of compounds have been developed based on the structure of menthol or using the structure and/or the cooling effect of menthol as a guide to the synthesis of a new cooling compound. Such synthetic physiological cooling agents include: menthol esters, menthol ethers, menthone derivatives, menthane derivatives, etc. These compounds have the advantage that they do not tend to have a mint-like odour and so are more pleasant to use; the topically applied product and the skin do not have to smell of mint to provide a cooling sensation.
A number of recent articles have reviewed ingredients claimed to provide a skin cooling sensation:                “Progress in Physiological Cooling agents”, Mark Ermann, Perfumery & Flavourist, Vol. 29, November/December 2004        “Cool Without Menthol & Cooler than Menthol and Cooling Compounds as Insect Repellents”, John C. Leffingwell, Leffingwell & Associates, 2006        
In order to obtain a strong cooling effect on the skin, quite high levels of physiological cooling agents need to be incorporated into the topically applied formulation. Menthol, being one of the more effective cooling agents, is often used from around 0.01% w/w upwards in the formulation. Synthetic cooling agents based around the activity of menthol, such as those mentioned above, are used at higher levels, typically 0.05% w/w and upwards and often up to 2%. Since these synthetic cooling agents are expensive, there is a need to find ways to enhance their perceived cooling effect on the skin.